US11780834B2ActiveUtilityA1
Solid forms of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol and processes for preparing fused tricyclic compounds comprising a substituted phenyl or pyridinyl moiety, including methods of their use
Est. expiryJun 21, 2038(~12 yrs left)· nominal 20-yr term from priority
Inventors:Cheol K. ChungJie XuHans IdingKyle Bradley Pascual ClaggMichael E. DalzielAlec FettesFrancis GosselinNgiap-Kie LimAndrew MccloryHaiming ZhangParoma ChakravartyKarthik NagapudiSarah Robinson
A61P 35/00C07D 205/04C07C 2601/02C07D 471/04A61K 31/437C07D 209/14C07B 2200/07C07D 209/16A61P 35/04C07D 403/14C07B 2200/13C07D 401/12
68
PatentIndex Score
0
Cited by
110
References
72
Claims
Abstract
Provided herein are solid forms, salts, and formulations of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol, processes and synthesis thereof, and methods of their use in the treatment of cancer.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A process for preparing a compound of formula (VIII) or a salt thereof, the process comprising:
(a) reacting a reaction mixture comprising a compound of formula (IV), a compound of formula (V) or a compound of formula (X), and an organic solvent to form a compound of formula (VI) according to step 1 below
wherein
B is substituted or unsubstituted indolyl, benzofuranyl, benzothiophenyl, aza-indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, or furopyrazinyl;
each of R 1a and R 1b is independently hydrogen, fluorine, chlorine, —OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, and —CN, C 3-6 cycloalkyl, or C 3-6 spirocycloalkyl,
n is an integer of 2 or 3,
each of R 2a and R 2b is independently hydrogen, halogen, —OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, —CN, C 3-6 cycloalkyl, or C 3-6 spirocycloalkyl,
R 3a and R 3b are independently hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, —CN, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl, C 3-6 heteroaryl, or C 3-6 spirocycloalkyl,
J is phenyl or pyridinyl;
each R 4 is independently hydrogen, halogen or C 1-3 alkyl,
s is an integer from 0 to 2,
LG is a leaving group,
LG and CHO are located in the para position with respect to each other on J on the compound of formula (V),
PG is an aldehyde protecting group,
LG and CH-PG are located in the para position with respect to each other on J on the compound formula (X), and
each asterisk independently represents a chiral center wherein the carbon bearing R 3a and R 3b is a chiral center when R 3a and R 3b are different; and
(b) reacting a reaction mixture comprising the compound of formula (VI), an organic solvent, and a compound of formula (VII) or a salt thereof to form a compound of formula (VIII) or a salt thereof according to step 2 below
wherein
G is C 1-3 alkyl,
p is 0 or 1,
E is substituted or unsubstituted azetidinyl or pyrrolidinyl,
each R 5 is independently hydrogen, halogen, —OH, —CN, C 1-5 alkoxy, or C 1-5 hydroxyalkyl,
v is an integer from 1 to 5, and
R 6 is halogen or —CN;
R 10 is hydrogen or C 1-3 alkyl.
2. The process of claim 1 , wherein B is a substituted or unsubstituted indolyl, benzofuranyl, or benzothiophenyl.
3. The process of claim 2 , wherein B is a substituted or unsubstituted indolyl.
4. The process wherein 1 , is a substituted or unsubstituted pyrrolopyridazinyl, pyrrolopyrimidinyl, or pyrrolopyrazinyl.
5. The process of claim 1 , wherein B is substituted with one or two substituents independently selected from fluorine, chlorine, C 1-3 alkyl, C 1-3 haloalkyl, —CN, —OH, C 1-3 alkoxy, or C 1-3 hydroxyalkyl.
6. The process of claim 1 , wherein each of R 1a and R 1b is independently hydrogen, —F, —Cl, —OH, —CN, —CH 3 , —CF 3 , —CHF 2 , —CH 2 F, or spirocyclopropyl.
7. The process of claim 1 , wherein n is 3.
8. The process of claim 1 , wherein:
9. The process of claim 1 , wherein each of R 2a and R 2b is hydrogen.
10. The process of claim 1 , wherein R 3a and R 3b are independently hydrogen or —CH 3 .
11. The process of claim 1 , wherein each R 4 is fluorine.
12. The process of claim 1 , wherein s is 2.
13. The process of claim 1 , wherein the leaving group is bromine.
14. The process of claim 1 , wherein p is 0.
15. The process of claim 1 , wherein the structure of the moiety of formula
of Compound (VII) and Compound (VIII) is:
wherein each R 5 is hydrogen.
16. The process of claim 1 , wherein v is 3.
17. The process of claim 1 , wherein R 6 is fluorine.
18. The process of claim 1 , wherein the compound of formula (VII) is a salt of an acid.
19. The process of claim 1 , wherein step 1 further comprises an acid catalyst.
20. The process of claim 1 , wherein step 2 further comprises a transition metal catalyst.
21. The process of claim 1 , wherein the compound of formula (IV) is:
or salt thereof, including stereoisomers thereof.
22. The process of claim 1 , wherein the compound of formula (V) is:
or a salt thereof.
23. The process of claim 1 , wherein the compound of formula (X) is:
24. The process of claim 1 , wherein the compound of formula (VI) is:
or a salt thereof, including stereoisomers thereof.
25. The process of claim 1 , wherein the compound of formula (VII) is:
or a salt thereof.
26. The process of claim 1 , wherein the compound of formula (VIII) is:
or a pharmaceutically acceptable salt thereof including stereoisomers thereof.
27. The process of claim 26 , further comprising contacting the compound of formula (VIII) with (2R-3R)-tartaric acid in the presence of an organic solvent.
28. The process of claim 1 , wherein the compound of formula (VIII) is:
or a pharmaceutically acceptable salt thereof.
29. The process of claim 28 , wherein the compound of formula (VIII) is:
30. The process of claim 1 , further comprising crystallizing the compound of formula (VIII) as the tartaric acid salt thereof.
31. A process for preparing a compound of formula (VIII) or a salt thereof, the process comprising reacting a reaction mixture comprising a compound of formula (IX) or a compound of formula (XI), a compound of formula (IV) and an organic solvent to form the compound of formula (VIII) or a salt thereof according to step 1 below
wherein:
B is substituted or unsubstituted indolyl, benzofuranyl, benzothiophenyl, aza-indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, furopyridazinyl, furopyrimidinyl, or furopyrazinyl;
each of R 1a and R 1b is independently hydrogen, halogen, —OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, and —CN, C 3-6 cycloalkyl, or C 3-6 spirocycloalkyl;
n is an integer of 2 or 3;
each of R 2a and R 2b is independently hydrogen, halogen, —OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, —CN, C 3-6 cycloalkyl, or C 3-6 spirocycloalkyl;
R 3a and R 3b are independently hydrogen, halogen, —OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, —CN, C 3-6 cycloalkyl, or C 3-6 spirocycloalkyl;
J is phenyl or pyridinyl;
each R 4 is independently hydrogen, halogen or C 1-3 alkyl;
s is an integer from 0 to 2;
G is C 1-3 alkyl;
p is 0 or 1;
E is substituted or unsubstituted azetidinyl or pyrrolidinyl;
each R 5 is independently hydrogen, halogen, —OH, —CN, C 1-5 alkoxy or C 1-5 hydroxyalkyl;
v is an integer from 1 to 5;
R 6 is halogen or —CN;
R 10 is H or C 1-3 alkyl;
the CHO moiety and the nitrogen atom linking J and G are located in the para position with respect to each other on J on the compound of formula (IX);
PG is an aldehyde protecting group,
CH-PG and the nitrogen atom linking J and G are located in the para position with respect to each other on J on the compound of formula (XI); and
each asterisk independently represents a chiral center wherein the carbon bearing R 3a and R 3b is a chiral center when R 3a and R 3b are different.
32. The process of claim 31 , wherein B is a substituted or unsubstituted indolyl, benzofuranyl, or benzothiophenyl.
33. The process of claim 32 , wherein B is a substituted or unsubstituted indolyl.
34. The process of claim 31 , wherein B is a substituted or unsubstituted pyrrolopyridazinyl, pyrrolopyrimidinyl, or pyrrolopyrazinyl.
35. The process of claim 31 , wherein B is substituted with one or two substituents independently fluorine, chlorine, C 1-3 alkyl, C 1-3 haloalkyl, —CN, —OH, C 1-3 alkoxy or C 1-3 hydroxyalkyl.
36. The process of claim 31 , wherein each of R 1a and R 1b is independently hydrogen, F, —Cl, —OH, —CN, —CH 3 , —CF 3 , —CHF 2 , —CH 2 F, or spirocyclopropyl.
37. The process of claim 31 , wherein n is 3.
38. The process of claim 31 , wherein:
39. The process of claim 31 , wherein each of R 2a and R 2b is hydrogen.
40. The process of claim 31 , wherein R 3a and R 3b are independently hydrogen or —CH 3 .
41. The process of claim 31 , wherein J is phenyl.
42. The process of claim 31 , wherein the structure of the moiety of formula
of Compound (VIII), Compound (IX), and Compound (XI) is:
wherein each R 5 is hydrogen.
43. The process of claim 31 , wherein each R 4 is fluorine.
44. The process of claim 31 , wherein s is 2.
45. The process of claim 31 , wherein p is 0.
46. The process of claim 31 , wherein v is 3.
47. The process of claim 31 , wherein R 6 is fluorine.
48. The process of claim 31 , wherein the compound of formula (IV) is:
or salt thereof, including stereoisomers thereof.
49. The process of claim 31 , wherein the compound of formula (IX) is:
or a salt thereof.
50. The process of claim 31 , wherein the compound of formula (XI) is:
or a salt thereof.
51. The process of claim 31 , wherein the compound of formula (VIII) is:
or a pharmaceutically acceptable salt thereof including stereoisomers thereof.
52. The process of claim 31 , further comprising contacting the compound of formula (VIII) with (2R-3R)-tartaric acid in the presence of an organic solvent.
53. The process of claim 31 , wherein the compound of formula (VIII) is:
or a pharmaceutically acceptable salt thereof.
54. The process of claim 53 , wherein the compound of formula (VIII) is:
55. The process of claim 31 , further comprising crystallizing the compound of formula (VIII) as the tartaric acid salt thereof.
56. A process for preparing a compound of formula (IX) or a salt thereof, the process comprising:
(1) reacting a reaction mixture comprising a compound of formula (X), an ethane-1,2-disulfonate salt of a compound of formula (VII), an organic solvent and a catalyst to form a compound of formula (XI) according to step 1 below
wherein
J is phenyl or pyridinyl;
each R 4 is independently hydrogen, halogen or C 1-3 alkyl,
s is an integer from 0 to 2,
LG is a leaving group, h
PG is an aldehyde protecting group,
LG and CH-PG are located in the para position with respect to each other on J,
G is C 1-3 alkyl,
p is 0 or 1,
E is substituted or unsubstituted azetidinyl or pyrrolidinyl,
each R 5 is independently hydrogen, halogen, —OH, —CN, C 1-5 alkoxy or C 1-5 hydroxyalkyl,
v is an integer from 1 to 5,
R 6 is halogen or —CN, and
R 10 is hydrogen or C 1 -C 3 alkyl; and
(2) deprotecting the compound of formula (XI) to form the compound of formula (IX) according to step 2 below
57. The process of claim 56 , wherein J is phenyl.
58. The process of claim 56 , wherein each R 4 is fluorine.
59. The process of claim 56 , wherein s is 2.
60. The process of claim 56 , wherein the leaving group is bromine.
61. The process of claim 56 , wherein p is 0.
62. The process of claim 56 , wherein the structure of the moiety of formula
of Compound (VIII), Compound (IX), and Compound (XI) is:
wherein each R 5 is hydrogen.
63. The process of claim 56 , wherein v is 3.
64. The process of claim 56 , wherein R 6 is fluorine.
65. The process of claim 56 , wherein the compound of formula (VII) is a salt of an acid.
66. The process of claim 56 , wherein the aldehyde protecting group is a trialkylorthoformate.
67. The process of claim 56 , wherein the step 1 catalyst is a transition metal catalyst.
68. The process of claim 56 , wherein the compound of formula (XI) is deprotected by contact with an acid.
69. The process of claim 56 , wherein the compound of formula (IX) is:
or a salt thereof.
70. A process for the preparation of Compound B,
wherein the process comprises the steps of:
step (1): contacting a compound
with p-toluenesulfonic acid (p-TsOH) and triethyl orthoformate ((EtO) 3 CH) in a solvent comprising toluene to yield a compound of formula
step (2): contacting the compound of formula
from step 1 with a compound of formula
and NaOt-Bu followed by BrettPhos Pd G3, in a solvent comprising toluene to yield a compound of formula
step (3): contacting the compound of formula
of step 2 with acetic acid in water to yield a compound of formula
step (4): contacting the compound of formula
of step (3) with a compound of formula
(4),
wherein the compound of formula (4) is prepared according to the process:
and L-Tartaric Acid in ethanol to yield the compound of formula (B).
71. The process of claim 70 , wherein the process further comprises recrystallization of Compound B in methanol and ethanol;
72. The process of claim 70 , wherein the process further comprises recrystallization of Compound B in MTBE, water, NaOH and ethanol;Cited by (0)
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